CD1d-reactive NKT cells with an invariant Valpha14 rearrangement (Valpha14i) represent a distinct subset of T lymphocytes that are likely to have important immune regulatory functions. The frequency of Valpha14i NKT cells, and of their human counterpart Valpha24i T cells, is reduced in a variety of autoimmune diseases. Restoration of the valpha14i NKT cells number by means of cell transfer or by forced expression of a transgenic rearranged Valpha14i TCR in the diabetes-prone NOD mice is protective of diabetes. Conversely, the Valpha14i NKT cell deficiency in CD14- NOD mice accelerates disease onset. Altogether, these results suggest that the number of Valpha14i NKT cells is of prime importance for the establishment of immunoregulation. However, little is known regarding the factors governing the maintenance of Valpha14i NKT cells. The overall goal of this grant application is to further understand the mechanisms that control the homeostasis of the Valpha14i NKT cell population in vivo. The experiments proposed examine several aspect of the homeostasis of Valpha14i NKT cells, including the role of IL-15 in the survival of this population, the possible competition between different IL-15 responsive cell populations, the control of the Valpha14i NKT cell number by regulatory CD4+CD25+ T cells and the role of a novel cytokine, IL-21, in Valpha14i NKT cell development and homeostasis. These studies will provide a comprehensive analysis of the mechanisms at play in the maintenance of the Valpha14i NKT cell population in vivo. Understanding such mechanisms might allow for the manipulation of the Valpha14i NKT cell number in vivo that could be exploited for the development of novel immune therapies for cancer and autoimmune diseases.